US 8,574,563 B2Granted

Hepatitis C virus inhibitors

AssigneeBristol-Myers Squibb Company

InventorsCarol Bachand, Makonen Belema, Daniel H. Deon, Andrew C. Good, Jason Goodrich, Clint A. James, Rico Lavoie, Omar D. Lopez, Alain Martel, Nicholas A. Meanwell, Van N. Nguyen, Jeffrey Lee Romine, Edward H. Ruediger, Lawrence B. Snyder, Denis R. St. Laurent, Fukang Yang, David R. Langley, Gan Wang, Lawrence G. Hamann

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Abstract

The present disclosure relates to compounds, compositions and methods for the treatment of hepatitis C virus (HCV) infection. Also disclosed are pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HCV infection.

Claims26

Dependent claims

A compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein
m and n are independently 0, 1, or 2;
o and p are independently 1, 2, or 3;
q and s are independently 0, 1, 2, 3, or 4;
u and v are independently 0, 1, 2, or 3;
each R1 and R2 is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, —NRaRb, (NRaRb)alkyl, and (NRaRb)carbonyl;
R3 and R4 are each independently selected from hydrogen and R9—C(O)—, and R9—C(S)—;
each R5 and R6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NRaRb, wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R7 and R8 are each independently selected from hydrogen, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, haloalkyl, (NRaRb)carbonyl, and trialkylsilylalkoxyalkyl;
and
each R9 is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NRcRd, (NRcRd)alkenyl, (NRcRd)alkyl, and (NRcRd)carbonyl.

8 more elements

A compound selected from

methyl((1S)-1-(((6S)-6-(4-(4′-(2-((6S)-5-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-azaspiro[2.4]hept-6-yl)-1H-imidazol-4-yl)-4-biphenylyl)-1H -imidazol-2-yl)-5-azaspiro[2.4]hept-5-yl)carbonyl)-2-methylpropyl)carbamate;
methyl((1S)-1-(((2S,5S)-2-(4-(4′-(2-((2S,5S)-1S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;
methyl(2-((6S)-6-(4-(4′-(2-((6S)-5-(((methoxycarbonyl)amino)acetyl)-5-azaspiro[2.4]hept-6-yl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-5-azaspiro[2.4]hept-5-yl)-2-oxoethyl)carbamate;
methyl((1S)-2-((6S)-6-(4-(4′-(2-((6S)-5-(N-(methoxycarbonyl)-L-alanyl)-5-azaspiro[2.4]hept-6-yl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-5-azaspiro[2.4]hept-5-yl)-1-methyl-2-oxoethyl)carbamate;
dimethyl (4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl(6S)-5-azaspiro[2.4]heptane-6,5-diyl((2S)-1-oxo-1,2-butanediyl)))biscarbamate;
methyl((1R)-1-(((6S)-6-(4-(4′-(2-((6S)-5-((2R)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-azaspiro[2.4]hept-6-yl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-5-azaspiro[2.4]hept-5-yl)carbonyl)-2-methylpropyl)carbamate;
dimethyl(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl(6S)-5-azaspiro[2.4]heptane-6,5-diyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))biscarbamate;
methyl((1R)-1-(((2S,5S)-2-(4-(4′-(2-((2S,5S)-1-((2R)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;
dimethyl(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl((2S,5 S)-5 -methyl-2, 1 -pyrrolidinediyl)((1R)-2-oxo-1 -phenyl-2,1 -ethanediyl)))biscarbamate;
dimethyl (4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl((2S,5S)-5 -methyl-2,1-pyrrolidinediyl)((2S)- 1-oxo-1,2-butanediyl)))biscarbamate;
methyl(2-((2S,5S)-2-(4-(4′-(2-((2S,5S)-1-(((methoxycarbonyl)amino)acetyl)-5-methyl-2-pyrrolidinyl)- 1H-imidazol-4-yl)-4-biphenylyl)-1 H-imidazol-2-yl)-5 -methyl-1-pyrrolidinyl)-2-oxoethyl)carbamate;
methyl(2-((2S,5S)-2-(4-(4′-(2-((2S,5S)-1-(2-((methoxycarbonyl)amino)-2-methylpropanoyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinyl)-1,1 -dimethyl-2-oxoethyl)carbamate;
methyl((1S)-2-((2S,5S)-2-(4-(4′-(2-((2S,5S)-1-(N-(methoxycarbonyl)-L-alanyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate;
4,4′-(4,4′-biphenyldiyl)bis(2-((2S,5 S)-5-methyl- 1-(3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazole);
4,4′-(4,4′-biphenyldiyl)bis(2-((2S,5 S)-5-methyl- 1-(phenylacetyl)-2-pyrrolidinyl)-1H-imidazole);
(2R,2′R)-1,1′-(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl((2S,5S)-5-methyl-2,1-pyrrolidinediyl)))bis(3-methyl-1-oxo-2-butanol);
(2S,2′S)-1,1′-(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl((2S ,5S)-5-methyl-2,1-pyrrolidinediyl)))bis(3-methyl-1-oxo-2-butanol);
2-((2S,5S)-1-acetyl-5-methyl-2-pyrrolidinyl)-4-(4′-(2-((2S,5S)-1-acetyl-5-methyl-2-pyrrolidinyl)-1H-imidazol-5 -yl)-4-biphenylyl)-1H-imidazole;
tert-butyl(2S)-2-(4-(4′-(2-((2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinyl)-4-(1,3-dioxan-2-ylmethyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate;
tert-butyl(2S)-2-(4-(4′-(2-((2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinyl)-4-(1,3-dioxolan-2-ylmethyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate;
tert-butyl(2S)-2-(4-(4′-(2-((2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-5-(2-methoxy-2-oxoethyl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate;
tert-butyl(2S)-2-(4-(4′-(2-((2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-5-propyl-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate;
ethyl 2-((2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinyl)-5-(4′-(2-((2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazole-4-carboxylate;
tert-butyl(2S)-2-(4-(4′-(2-((2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-3′-fluoro-4-biphenylyl)-1H-imidazol-2-yl)-4,4-difluoro-1-pyrrolidinecarboxylate;
2-((2S)-4,4-difluoro-2-pyrrolidinyl)-4-(3′-fluoro-4′-(2-((2S)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazole;
(1R)-2-((2S)-2-(4-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-5-methyl-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N-diethyl-2-oxo-1-phenylethanamine;
1-((1R)-2-((2S)-2-(4-(4′-(4-methyl-2-((2S)-1-((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)piperidine;
methyl((1R)-2-((2S)-2-(4-(4′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-5-methyl-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate;
methyl((1S)-2-((2S)-2-(4-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-4-methyl-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate;
methyl((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-5-methyl-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;
methyl((1S,2R)-2-methoxy-1-(((2S)-2-(4-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-threonyl)-2-pyrrolidinyl)-4-methyl-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate;
(1R,1′R)-2,2′-(4,4′-biphenyldiylbis((4-methyl-1H-imidazole-5,2-diyl)(2S)-2,1-pyrrolidinediyl))bis(N,N-dimethyl-2-oxo-1-phenylethanamine);
(1R,1′R)-2,2′-(4,4′-biphenyldiylbis((4-methyl-1H-imidazole-5,2-diyl)(2S)-2,1-pyrrolidinediyl))bis(N,N-diethyl-2-oxo-1-phenylethanamine);
1,1′-(4,4′-biphenyldiylbis((4-methyl- 1H-imidazole-5,2-diyl)(2S)-2,1-pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))dipiperidine;
dimethyl(4,4′-biphenyldiylbis((4-methyl-1H-imidazole-5,2-diyl)(2S)-2,1-pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))biscarbamate;
methyl((1S)-2-((2S)-2-(4-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-5-methyl-1H-imidazol-4-yl)-4-biphenylyl)-5-methyl- 1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate;
methyl((1S)-1-(((2S)-2-(4-(4′-(2-((2S)- 1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-4-methyl-1H-imidazol-5-yl)-4-biphenylyl)-5-methyl-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;
methyl((1S,2R)-2-methoxy-1-(((2S)-2-(4-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-threonyl)-2-pyrrolidinyl)-5-methyl-1H-imidazol-4-yl)-4-biphenylyl)-5-methyl-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate;
methyl((1S)-1-(((2S)-2-(4-(1,3-dioxan-2-ylmethyl)-5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;
methyl((1S,2R)-1-(((2S)-2-(4-(2,2-dimethoxyethyl)-5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-threonyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methoxypropyl)carbamate;
methyl((1S)-1-(((2S)-2-(4-(2,2-dimethoxyethyl)-5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;
methyl(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-threonyl)-2-pyrrolidinyl)-4(4′(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-threonyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-5-yl)acetate;
methyl(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-4-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-5-yl)acetate;
methyl((1S)-2-((2S)-2-(4-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-4-propyl-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate;
(1R)-2-((2S)-2-(4-(4′-(2-((2S)-1-2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-5-propyl-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N-diethyl-2-oxo-1-phenylethanamine;
methyl((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-5-propyl-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;
methyl((1S)-1-(((2S)-4,4-difluoro-2-(4-(3′-fluoro-4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;
(1R)-2-((2S)-2-(4-(4′-(2-((2S)-1-2R)-2-(diethylamino)-2-phenylacetyl)-4,4-difluoro-2-pyrrolidinyl)-1H-imidazol-4-yl)-3-fluoro-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N-diethyl-2-oxo-1-phenylethanamine;
methyl((1 S)-1-(((2S)-2-(4-(hydroxymethyl)-5 -(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3 -methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;
methyl((1S)-2-((2S)-2-(4-(4′-(4-(hydroxymethyl)-2-((2S)- 1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5 -yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate;
(N,N′-(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl(2S)-2,1 -pyrrolidinediyl((2S)-3-methyl-1-oxo-1,2-butanediyl)))di(2-pyrimidinamine);
N,N′-(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl(2S)-2,1 -pyrrolidinediyl((1S)-1-cyclopropyl-2-oxo-2,1 -ethanediyl)))di(2-pyrimidinamine);
N,N′-(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl(2S)-2,1 -pyrrolidinediyl((2S)- 1-oxo-1,2-propanediyl)))di(2-pyrimidinamine);
N,N′-(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl(2S)-2,1-pyrrolidinediyl((2S)-1-oxo-1,2-butanediyl)))di(2-pyrimidinamine);
N,N′-(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl(2S)-2,1-pyrrolidinediyl((2S)-3-methoxy-1-oxo-1,2-propanediyl)))di(2-pyrimidinamine);
and
N,N′-(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl(2S)-2,1-pyrrolidinediyl((2S,3R)-3-methoxy-1-oxo-1,2-butanediyl)))di(2-pyrimidinamine);
or a pharmaceutically acceptable salt thereof.

55 more elements

Dependencies are inferred from the claim text.

Facts

Application: 13/609,957Filed 11 Sep 2012 · division
Priority: 11 Aug 2006
Published: US 2013/0004457 A13 Jan 2013
Granted: 5 Nov 2013
Term ends: Not estimatedThe source records don’t support an estimate.

Classification21 codes

A61K 31/506
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: not condensed and containing further heterocyclic rings
A61K 31/13
Medicinal preparations containing organic active ingredients: amines
A61K 31/4178
1,3-Diazoles: not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
A61K 31/427
Thiazoles: not condensed and containing further heterocyclic rings

Family

Application60/836,996Us provisional application · filed 11 Aug 2006
Application11/835,462Parent of this continuation-in-part · filed 8 Aug 2007
Application12/030,232Parent of this division · filed 13 Feb 2008
US 2013/0004457 A1Pre-grant publication · published 3 Jan 2013
US 8,303,944 B2Parent of this division
US 8,329,159 B2Parent of this continuation-in-part
Application12/030,232Parent of this continuation-in-part
US 2008/0050336 A1Published application
US 2009/0068140 A1Published application
US 8,574,563 B2This patent

From the US filing history. Foreign family members aren’t listed.